ES2963218T3 - Productos intermedios para obtener compuestos de benzaldehído sustituidos y métodos para su uso en el aumento de la oxigenación tisular - Google Patents
Productos intermedios para obtener compuestos de benzaldehído sustituidos y métodos para su uso en el aumento de la oxigenación tisular Download PDFInfo
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- ES2963218T3 ES2963218T3 ES20167746T ES20167746T ES2963218T3 ES 2963218 T3 ES2963218 T3 ES 2963218T3 ES 20167746 T ES20167746 T ES 20167746T ES 20167746 T ES20167746 T ES 20167746T ES 2963218 T3 ES2963218 T3 ES 2963218T3
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- 238000000034 method Methods 0.000 title abstract description 26
- 239000000543 intermediate Substances 0.000 title abstract description 12
- 150000003935 benzaldehydes Chemical class 0.000 title abstract description 9
- 230000000287 tissue oxygenation Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 121
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 108010054147 Hemoglobins Proteins 0.000 abstract description 28
- 102000001554 Hemoglobins Human genes 0.000 abstract description 28
- 230000003281 allosteric effect Effects 0.000 abstract description 14
- 238000011282 treatment Methods 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 9
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000006213 oxygenation reaction Methods 0.000 abstract 1
- -1 protons Chemical compound 0.000 description 62
- 239000000203 mixture Substances 0.000 description 43
- 108010016797 Sickle Hemoglobin Proteins 0.000 description 34
- 150000003839 salts Chemical class 0.000 description 32
- 229910052760 oxygen Inorganic materials 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 26
- 239000001301 oxygen Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 22
- 125000005843 halogen group Chemical group 0.000 description 17
- 239000000546 pharmaceutical excipient Substances 0.000 description 17
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 13
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- 101150100019 NRDC gene Proteins 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
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- 125000005842 heteroatom Chemical group 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
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- 125000003118 aryl group Chemical group 0.000 description 8
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
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- 239000002585 base Substances 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
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- 125000004438 haloalkoxy group Chemical group 0.000 description 5
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
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- 238000006116 polymerization reaction Methods 0.000 description 5
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- 239000000725 suspension Substances 0.000 description 5
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- FMISYJFGLRUTEK-UHFFFAOYSA-N 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde Chemical compound C1=C(C=O)C(OC)=CC=C1OCC1=CC=CN=C1C1=CC=NN1C(C)C FMISYJFGLRUTEK-UHFFFAOYSA-N 0.000 description 4
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 4
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
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- 125000000623 heterocyclic group Chemical group 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
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- 229910052702 rhenium Inorganic materials 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- FWCVZAQENIZVMY-UHFFFAOYSA-N 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]benzaldehyde Chemical compound CC(C)N1N=CC=C1C1=NC=CC=C1COC1=CC=CC(O)=C1C=O FWCVZAQENIZVMY-UHFFFAOYSA-N 0.000 description 3
- UKTHRMMETXCGBZ-UHFFFAOYSA-N 3-(chloromethyl)-2-(2-propan-2-ylpyrazol-3-yl)pyridine;hydrochloride Chemical compound Cl.CC(C)N1N=CC=C1C1=NC=CC=C1CCl UKTHRMMETXCGBZ-UHFFFAOYSA-N 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- QIQZUABMLGJKJP-UHFFFAOYSA-N (2-bromopyridin-3-yl)methanol Chemical compound OCC1=CC=CN=C1Br QIQZUABMLGJKJP-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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KR20190041548A (ko) * | 2013-03-15 | 2019-04-22 | 글로벌 블러드 테라퓨틱스, 인크. | 헤모글로빈 조정을 위한 화합물 및 이의 용도 |
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CA2902874C (en) * | 2013-03-15 | 2021-04-20 | Global Blood Therapeutics, Inc. | Substituted pyridinyl-6-methoxy-benzaldehyde derivatives and pharmaceutical compositions thereof useful for the modulation of hemoglobin |
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US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
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PE20151907A1 (es) * | 2013-03-15 | 2016-01-20 | Global Blood Therapeutics Inc | Compuestos y usos de estos para la modulacion de la hemoglobina |
EA201591426A1 (ru) | 2013-03-15 | 2016-02-29 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
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2017
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2018
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2023
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